Mitotic control of RUNX2 phosphorylation by both CDK1/cyclin B kinase and PP1/PP2A phosphatase in osteoblastic cells

Rajgopal, Arun; Young, Daniel W.; Mujeeb, Khawaja A.; Stein, Janet L.; Lian, Jane B.; Wijnen, André J. van

doi:10.1002/jcb.21137

Cited by 59 publications

(43 citation statements)

References 26 publications

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“…1C, lanes 7 and 8). This result is consistent with studies that showed that the C termini of RUNX1 and RUNX2 harbor mitotic kinase CDK1 phosphorylation sites (13)(14)(15)(16).…”

Section: Significancesupporting

confidence: 92%

“…The reason why RUNX proteins are present at non-DNA sites (i.e., mitotic apparatus) during mitosis is unknown. An intriguing observation is the hyperphosphorylation of RUNX proteins during mitosis (13,14). RUNX2 is phosphorylated by mitotic kinase CDK1-cyclin B1 (14, 15) and dephosphorylated at mitotic exit by the PP1/PP2A phosphatase (14).…”

mentioning

confidence: 99%

“…An intriguing observation is the hyperphosphorylation of RUNX proteins during mitosis (13,14). RUNX2 is phosphorylated by mitotic kinase CDK1-cyclin B1 (14,15) and dephosphorylated at mitotic exit by the PP1/PP2A phosphatase (14). CDK1-mediated phosphorylation of RUNX2 enhanced DNA binding activity, suggesting a role for RUNX2 in G 2 /M progression (15).…”

mentioning

confidence: 99%

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Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Chuang

Khor

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Runt-related transcription factors (RUNX) are master regulators of development and major players in tumorigenesis. Interestingly, unlike most transcription factors, RUNX proteins are detected on the mitotic chromatin and apparatus, suggesting that they are functionally active in mitosis. Here, we identify key sites of RUNX phosphorylation in mitosis. We show that the phosphorylation of threonine 173 (T173) residue within the Runt domain of RUNX3 disrupts RUNX DNA binding activity during mitotic entry to facilitate the recruitment of RUNX proteins to mitotic structures. Moreover, knockdown of RUNX3 delays mitotic entry. RUNX3 phosphorylation is therefore a regulatory mechanism for mitotic entry. Cancer-associated mutations of RUNX3 T173 and its equivalent in RUNX1 further corroborate the role of RUNX phosphorylation in regulating proper mitotic progression and genomic integrity.C ell division is a highly ordered process comprising multiple steps that lead to dramatic changes to the cell architecture. Events such as cell rounding, chromatin condensation, spindle assembly, nuclear envelope disassembly, and cytokinesis involve numerous proteins, whose activities are tightly coordinated by mitotic kinases and proteasome-mediated degradation (1). Given that most transcription has stopped (2), the roles of transcription factors during mitosis are ill explored.Runt-related transcription factors (RUNX) are master regulators of cell-fate decisions (3). Mutation or dysregulation of RUNX genes have been associated with diverse cancer types (3). Unlike many transcription factors (e.g., Ets-1 and Oct-1) (4), RUNX proteins are retained at the condensed mitotic chromatin, where they maintain epigenetic memory and ensure proper transmission of gene expression patterns to progeny cells; RUNX2 binds to the promoters of various cell cycle-and cell fate-related genes and regulates histone modifications during mitosis (5); RUNX2 and RUNX3 bind to regulatory regions of rRNA genes and are associated with their repression (6, 7). RUNX1 positively regulates the transcription of various spindle assembly checkpoint genes, such as BUB1 and NEK6 (8). These findings suggest that RUNX proteins are important for the accurate transmission of genetic information during mitosis and that defects in RUNX genes might contribute to aneuploidy and loss of cell identity.Aside from binding to the chromatin, RUNX proteins also associate with microtubules (9, 10). RUNX3 molecules are detected at key mitotic structures such as the centrosome, mitotic spindle, and midbody (11). Likewise, RUNX-binding partner CBFβ was found at the midbody and implicated in cytokinesis (12). The reason why RUNX proteins are present at non-DNA sites (i.e., mitotic apparatus) during mitosis is unknown. An intriguing observation is the hyperphosphorylation of RUNX proteins during mitosis (13,14). RUNX2 is phosphorylated by mitotic kinase CDK1-cyclin B1 (14, 15) and dephosphorylated at mitotic exit by the PP1/PP2A phosphatase (14). CDK1-mediated phosphorylation of RUNX2 enhanc...

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“…1C, lanes 7 and 8). This result is consistent with studies that showed that the C termini of RUNX1 and RUNX2 harbor mitotic kinase CDK1 phosphorylation sites (13)(14)(15)(16).…”

Section: Significancesupporting

confidence: 92%

mentioning

confidence: 99%

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Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Chuang

Khor

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…RUNX2 activity was shown to be regulated by p38 MAPK, ERK1/2, 34 cdc2 35 and sequentially by Cdk1/cyclinB and PP2A phosphatase. 36 Phosphorylation of S104 and S451 inhibits the activity of RUNX2 by preventing association with the co-factor Core-binding factor, β subunit. 37 We found that Wip1 phosphatase can dephosphorylate S432 of RUNX2, another inhibitory site.…”

Section: Potential Benefits Of Elevated Levels Of Wip1 In Normal Tissmentioning

confidence: 99%

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x_Lratio

et al. 2012

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Wip1 is a stress-response phosphatase that negatively regulates several tumor suppressors, including p53. In a sizeable fraction of tumors, overexpression or amplification of Wip1 compromises p53 functions; inhibition of Wip1 activity is an attractive strategy for improving treatment of these tumors. However, over half of human tumors contain mutations in the p53 gene or have lost both alleles. Recently, we observed that in cancer cells lacking wild-type p53, reduction of Wip1 expression was ineffective, whereas, surprisingly, overexpression of Wip1 increased anticancer drug sensitivity. The increased sensitivity resulted from activation of the intrinsic pathway of apoptosis through increased levels of the pro-apoptotic protein Bax and decreased levels of the anti-apoptotic protein Bcl-x L . We showed that interaction of Wip1 and the transcription factor RUNX2, specifically through dephosphorylation of RUNX2 phospho-S432, resulted in increased expression of Bax. Interestingly, overexpression of Wip1 increased drug sensitivity only in the p53-negative tumor cells while protecting the wild-type, p53-containing normal cells from drug-induced collateral injury. Here, we provide evidence that Wip1 overexpression decreases expression of Bcl-x L through negative regulation of NFκB activity. Thus, Wip1 overexpression increases the sensitivity of p53-negative cancer cells to anticancer drugs by separately affecting Bax and Bcl-x L protein levels.

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“…(19) Runx2 is tightly regulated during the cell cycle at both the transcriptional and posttranslational levels. (20) Phosphorylation of Runx2 during the cell cycle by distinct cyclin/CDK complexes regulates its activity or stability by a proteasome-dependent mechanism. (21) Genetic analysis has revealed that Runx2 is degraded through a Smurf-mediated ubiquitination pathway.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Ann

Kim

Choi

et al. 2010

Journal of Bone and Mineral Research

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Notch1 genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch1 signaling in osteogenesis is not well defined. Notch1 controls osteoblast differentiation by affecting Runx2, but the question arises whether normal osteoblastic differentiation can occur regardless of the presence of Notch1. In this study, we observed the downregulation of Notch1 signaling during osteoblastic differentiation. BMPR‐IB/Alk6‐induced Runx2 proteins reduced Notch1 activity to a marked degree. Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1‐IC‐RBP‐Jk complex. Using deletion mutants, we also determined that the N‐terminal domain of Runx2 was crucial to the binding and inhibition of the N‐terminus of the Notch1 intracellular domain. Notably, upregulation of the Runx2 protein level paralleled reduced expression of Hes1, which is a downstream target of Notch1, during osteoblast differentiation. Collectively, our data suggest that Runx2 is an inhibitor of the Notch1 signaling pathway during normal osteoblast differentiation. © 2011 American Society for Bone and Mineral Research.

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Mitotic control of RUNX2 phosphorylation by both CDK1/cyclin B kinase and PP1/PP2A phosphatase in osteoblastic cells

Cited by 59 publications

References 26 publications

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x_Lratio

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

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Mitotic control of RUNX2 phosphorylation by both CDK1/cyclin B kinase and PP1/PP2A phosphatase in osteoblastic cells

Cited by 59 publications

References 26 publications

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xLratio

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

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Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x_Lratio